Glioblastoma, GBM, is the most frequent brain malignancy in adults. Patients with these tumors survive only, approximately, one year after diagnosis and rarely survive beyond two years. This poor prognosis is, in part, due to our insufficient understanding of the complex aggressive nature of these tumors and the lack of effective therapy. In GBM, over-expression of EGFR and/or its constitutively activated variant EGFRvIII is a major characteristic and is associated with tumorigenesis and more aggressive phenotypes, such as, invasiveness and therapeutic resistance. Consequently, both have been major targets for GBM therapy, however, clinical trials of EGFR- and EGFRvIII-targeted therapies have yielded unsatisfactory results and the molecular basis for the poor results is still unclear. Thus, in this review, we will summarize results of recent clinical trials and recent advances made in the understanding of the EGFR/EGFRvIII pathways with a key focus on those associated with intrinsic resistance of GBM to EGFR-targeted therapy. For example, emerging evidence indicates an important role that PTEN plays in predicting GBM response to EGFR-targeted therapy. Aberrant Akt/mTOR pathway has been shown to contribute to the resistant phenotype. Also, several studies have reported that EGFR/EGFRvIIIs cross-talk with the oncogenic transcription factor STAT3 and receptor tyrosine kinases (c-Met and PDGFR) potentially lead to GBM resistance to anti-EGFR therapy. Other emerging mechanisms, including one involving HMG-CoA reductase, will also be discussed in this mini-review. These recent findings have provided new insights into the highly complex and interactive nature of the EGFR pathway and generated rationales for novel combinational targeted therapies for these tumors.